Prolastin.18 the Mean in Vivo Recovery 18,19 of Alpha1-PI Was 4.2 Mg (Immunologic)/Dl Per Mg (Functional)/Kg Body Weight Administered

08937789 (Rev. January 2005) ipated in a study of acute and/or chronic replacement therapy with Prolastin.18 The mean in vivo recovery 18,19 of alpha1-PI was 4.2 mg (immunologic)/dL per mg (functional)/kg body weight administered. The 18,19 Alpha1-Proteinase Inhibitor (Human) half-life of alpha1-PI in vivo was approximately 4.5 days. Based on these observations, a program of chronic replacement therapy was developed. Nineteen of the subjects in these studies received w Prolastin replacement therapy, 60 mg/kg body weight, once weekly for up to 26 weeks (average 24 weeks Prolastin of therapy). With this schedule of replacement therapy, blood levels of alpha1-PI were maintained above 18-20 80 mg/dL (based on the commercial standards for alpha1-PI immunologic assay). Within a few FOR INTRAVENOUS USE ONLY weeks of commencing this program, bronchoalveolar lavage studies demonstrated significantly increased levels of alpha -PI and functional antineutrophil elastase capacity in the epithelial lining fluid 1 5 8 1 of the lower respiratory tract of the lung, as compared to levels prior to commencing the program of 18-20 chronic replacement therapy with Alpha1-Proteinase Inhibitor (Human), Prolastin. All 23 individuals who participated in the investigations were immunized with Hepatitis B Vaccine and received a single dose of Hepatitis B Immune Globulin (Human) on entry into the investigation. Although no other steps were taken to prevent hepatitis, neither hepatitis B nor non-A, non-B hepatitis occurred in any of the subjects.18,19 All subjects remained seronegative for HIV antibody. None of the subjects developed any detectable antibody to alpha1-PI or other serum protein. Long-term controlled clinical trials to evaluate the effect of chronic replacement therapy with Prolastin on the development of or progression of emphysema in patients with congenital alpha1-antitrypsin deficiency have not been performed. Estimates of the sample size required of this rare disorder and the slow, progressive nature of the clinical course have been considered impediments in the ability to DESCRIPTION conduct such a trial.21 Studies to monitor the long-term effects will continue as part of the postapproval process. Alpha1-Proteinase Inhibitor (Human), Prolastinw is a sterile, stable, lyophilized preparation of purified human Alpha1-Proteinase Inhibitor (alpha1-PI), also known as alpha1-antitrypsin. Prolastin is intended INDICATIONS AND USAGE for use in therapy of congenital alpha1-antitrypsin deficiency. Prolastin is prepared from pooled human plasma of normal donors by modification and refinements Congenital Alpha1-Antitrypsin Deficiency 1 of the cold ethanol method of Cohn. Part of the fractionation may be performed by another licensed Alpha1-Proteinase Inhibitor (Human), Prolastin is indicated for chronic replacement therapy of manufacturer. In order to reduce the potential risk of transmission of infectious agents, Prolastin has individuals having congenital deficiency of alpha1-PI (alpha1-antitrypsin deficiency) with clinically been heat-treated in solution at 60�0.5°C for not less than 10 hours. However, no procedure has demonstrable panacinar emphysema. Clinical and biochemical studies have demonstrated that with been found to be totally effective in removing viral infectivity from plasma fractionation products. In such therapy, it is possible to increase plasma levels of alpha1-PI, and that levels of functionally active 18-20 vitro studies designed to evaluate the capacity of the Prolastin manufacturing process to alpha1-PI in the lung epithelial lining fluid are increased proportionately. As some individuals with remove/inactivate viruses have been conducted to provide additional assurance of the viral safety alpha1-antitrypsin deficiency will not go on to develop panacinar emphysema, only those with profile as shown in the table below. evidence of such disease should be considered for chronic replacement therapy with Prolastin.22 Subjects with the PiMZ or PiMS phenotypes of alpha1-antitrypsin deficiency should not be considered Process Step Log10 Virus Reduction for such treatment as they appear to be at small risk for panacinar emphysema.22 Clinical data are * Human immunodeficiency virus, type 1 HIV-1* BVDV** PRV*** Reo† HAV†† PPV‡ ** Bovine viral diarrhea virus (BVDV) was chosen not available as to the long-term effects derived from chronic replacement therapy of individuals with to model hepatitis C virus Fractionation of alpha1-antitrypsin deficiency with Prolastin. Only adult subjects have received Prolastin to date. Effluent I to II+III 3.4 3.5 3.9 2.1 1.4 1.0 *** Pseudorabies virus (PRV) was used as a surrogate for hepatitis B virus and the human Prolastin is not indicated for use in patients other than those with PiZZ, PiZ(null) or Pi(null)(null) PEG Precipitation 4.4 3.2 3.4 3.4 3.1 3.3 herpes viruses phenotypes. ≥ ≥ ≥ ≥ ≥ † Reovirus type 3 (Reo) was chosen to model Depth Filtration 4.7 4.1 4.7 4.0 2.8 4.3 non-enveloped viruses Pasteurization ≥6.3 4.8 ≥4.8 N/A N/A N/A †† Human hepatitis A virus (HAV). CONTRAINDICATIONS ‡ Porcine parvovirus (PPV) was selected as a Accumulated Log10 surrogate for human parvovirus B19 Individuals with selective IgA deficiencies who have known antibody against IgA (anti-IgA antibody) Reduction ≥18.8 15.6 ≥16.8 ≥9.5 ≥7.3 ≥8.6 should not receive Alpha1-Proteinase Inhibitor (Human), Prolastin, since these patients may experience severe reactions, including anaphylaxis, to IgA which may be present. The specific activity of Prolastin is �0.35 mg functional alpha1-PI/mg protein and when reconstituted as directed, the concentration of alpha1-PI is �20 mg/mL. When reconstituted, Prolastin has a pH of WARNINGS 6.6–7.4, a sodium content of 100–210 mEq/L, a chloride content of 60–180 mEq/L, a sodium Because this product is made from human blood, it may carry a risk of transmitting infectious phosphate content of 0.015–0.025 M, a polyethylene glycol content of not more than (NMT) 5 ppm, agents, e.g. viruses, and, theoretically, the Creutzfeldt-Jakob (CJD) agent. The risk that such and NMT 0.1% sucrose. Prolastin contains small amounts of other plasma proteins including alpha2 products will transmit an infectious agent has been reduced by screening plasma donors for plasmin inhibitor, alpha1-antichymotrypsin, C1-esterase inhibitor, haptoglobin, antithrombin III, alpha1 prior exposure to certain viruses, by testing for the presence of certain current virus infections, lipoprotein, albumin, and IgA.1 and by inactivating and/or removing certain viruses. Despite these measures, such products can Each vial of Prolastin contains the labeled amount of functionally active alpha1-PI in milligrams per vial still potentially transmit disease. There is also the possibility that unknown infectious agents (mg/vial), as determined by capacity to neutralize porcine pancreatic elastase.1 Prolastin contains no may be present in such products. Individuals who receive infusions of blood or plasma products preservative and must be administered by the intravenous route. may develop signs and/or symptoms of some viral infections, particularly hepatitis C. ALL infections thought by a physician possibly to have been transmitted by this product should be CLINICAL PHARMACOLOGY reported by the physician or other healthcare provider to Talecris Biotherapeutics, Inc. [1-800 520-2807]. Alpha1-antitrypsin deficiency is a chronic, hereditary, usually fatal, autosomal recessive disorder in which a low concentration of alpha1-PI (alpha1-antitrypsin) is associated with slowly progressive, severe The physician should discuss the risks and benefits of this product with the patient, before panacinar emphysema that most often manifests itself in the third to fourth decades of life.2-9 [Although prescribing or administering it to a patient. the terms “Alpha -Proteinase Inhibitor” and “alpha -antitrypsin” are used interchangeably in the scientific 1 1 Alpha -Proteinase Inhibitor (Human), Prolastin has been heat-treated in solution at 60°C for 10 hours literature, the hereditary disorder associated with a reduction in the serum level of alpha -PI is conven 1 1 in order to reduce the potential for transmission of infectious agents.1 No cases of hepatitis, either tionally referred to as “alpha -antitrypsin deficiency” while the deficient protein is referred to as “Alpha 1 1 hepatitis B or hepatitis C, have been recorded to date in individuals receiving Prolastin.18 However, as Proteinase Inhibitor”10]. The emphysema is typically worse in the lower lung zones.4,8,9 The pathogenesis all individuals received prophylaxis against hepatitis B, no conclusion can be drawn at this time of development of emphysema in alpha -antitrypsin deficiency is not well understood at this time. It is 1 regarding potential transmission of hepatitis B virus. believed, however, to be due to a chronic biochemical imbalance between elastase (an enzyme capable of degrading elastin tissues, released by inflammatory cells, primarily neutrophils, in the lower respiratory PRECAUTIONS tract) and alpha -PI (the principal inhibitor of neutrophil elastase), which is deficient in alpha -antitrypsin 1 1 General disease.11-15 As a result, it is believed that alveolar structures are unprotected from chronic exposure to elastase released from a chronic, low-level burden of neutrophils in the lower respiratory tract, resulting 1. Administer within 3 hours after reconstitution. Do not refrigerate after reconstitution. in progressive degradation of elastin tissues.11-15 The eventual outcome is the development of 2. Administer only by the intravenous route. emphysema. Neonatal hepatitis with cholestatic jaundice appears in approximately 10% of newborns with 15 15 3. As with any colloid solution, there will be an increase in plasma volume following intravenous alpha1-antitrypsin deficiency. In some adults, alpha1-antitrypsin deficiency is complicated by cirrhosis. 23 administration of Alpha1-Proteinase Inhibitor (Human), Prolastin. Caution should therefore be 15 A large number of phenotypic variants of alpha1-antitrypsin deficiency exists. The most severely used in patients at risk for circulatory overload. affected individuals are those with the PiZZ variant, typically characterized by alpha1-PI serum levels 15 4. Prolastin should be given alone, without mixing with other agents or diluting solutions. �35% normal. Epidemiologic studies of individuals with various phenotypes of alpha1-antitrypsin deficiency have demonstrated that individuals with endogenous serum levels of alpha1-PI �50 mg/dL 5. Product administration and handling of the needles must be done with caution. Percutaneous (based on commercial standards) have a risk of �80% of developing emphysema over a puncture with a needle contaminated with blood can transmit infectious virus including HIV (AIDS) 3-6,8,9,16 lifetime. However, individuals with endogenous alpha1-PI levels �80 mg/dL, in general, do not and hepatitis. Obtain immediate medical attention if injury occurs. manifest an increased risk for development of emphysema above the general population background Place needles in sharps container after single use. Discard all equipment including any 5,15 risk. From these observations, it is believed that the “threshold” level of alpha1-PI in the serum reconstituted Prolastin product in accordance with biohazard procedures. required to provide adequate anti-elastase activity in the lung of individuals with alpha -antitrypsin 1 Carcinogenesis, Mutagenesis, Impairment of Fertility deficiency is about 80 mg/dL (based on commercial standards for immunologic assay of 12,15,17 alpha1-PI). Long-term studies in animals to evaluate carcinogenesis, mutagenesis, or impairment of fertility have not been conducted. In clinical studies of Alpha1-Proteinase Inhibitor (Human), Prolastin, 23 subjects with the PiZZ variant of congenital deficiency of alpha1-antitrypsin deficiency and documented destructive lung disease partic

Glover Printing, Inc. Client: Talecris Biotherapeutics, Inc. Edits: Job No. 4078 Cat. No. 08937789 Fonts: Attriumvirate Color: BLACK ID: 1,5,8 Size: 10.25” x 11.25” Date(s): 11/21, 11/28, 11/30, 12/19/06, 1/2, 1/10, 2/5, 2/6/07 Proof 8 Pregnancy Category C

Animal reproduction studies have not been conducted with Alpha1-Proteinase Inhibitor (Human), Prolastinw. It is also not known whether Prolastin can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Prolastin should be given to a pregnant woman only if clearly needed. Nursing Mothers It is not known whether Prolastin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Prolastin is administered to a nursing woman. Pediatric Use Safety and effectiveness in the pediatric population have not been established. ADVERSE REACTIONS A number of factors beyond our control could reduce the efficacy of this product or even result in an Therapeutic administration of Alpha1-Proteinase Inhibitor (Human), Prolastin, 60 mg/kg weekly, has been demonstrated to be well tolerated. In clinical studies, six reactions were observed with 517 ill effect following its use. These include improper storage and handling of the product after it leaves our infusions of Prolastin, or 1.16%. None of the reactions was severe.18 The adverse reactions reported hands, diagnosis, dosage, method of administration, and biological differences in individual patients. included delayed fever (maximum temperature rise was 38.9°C, resolving spontaneously over 24 hours) Because of these factors, it is important that this product be stored properly, that the directions be occurring up to 12 hours following treatment (0.77%), light-headedness (0.19%), and dizziness followed carefully during use, and that the risk of transmitting viruses be carefully weighed before the (0.19%).18 Mild transient leukocytosis and dilutional anemia several hours after infusion have also been product is prescribed. 18 noted. Since market entry, occasional reports of other ﬂu-like symptoms, allergic-like reactions, chills, HOW SUPPLIED dyspnea, rash, tachycardia, and, rarely, hypotension have also been received. Rare cases of transient increase in blood pressure or hypertension and chest pain have also been reported. Alpha1-Proteinase Inhibitor (Human), Prolastin is supplied in the following single use vials with the total alpha1-PI functional activity, in milligrams, stated on the label of each vial. A suitable volume of DOSAGE AND ADMINISTRATION Sterile Water for Injection, USP, is provided.

FOR INTRAVENOUS USE ONLY Approximate Alpha1-PI NDC Number Functional Activity Diluent Each bottle of Alpha1-Proteinase Inhibitor (Human), Prolastin has the functional activity, as determined by inhibition of porcine pancreatic elastase,1 stated on the label of the bottle. 13533-601-30 500 mg 20 mL 13533-601-35 1000 mg 40 mL The “threshold” level of alpha1-PI in the serum believed to provide adequate anti-elastase activity in the lung of individuals with alpha1-antitrypsin deficiency is 80 mg/dL (based on commercial standards STORAGE for alpha -PI immunologic assay).12,15,17 However, assays of alpha -PI based on commercial 1 1 Prolastin should be stored at temperatures not to exceed 25°C (77°F). Freezing should be avoided standards measure antigenic activity of alpha -PI, whereas the labeled potency value of alpha -PI is 1 1 as breakage of the diluent bottle might occur. expressed as actual functional activity, i.e., actual capacity to neutralize porcine pancreatic elastase. As functional activity may be less than antigenic activity, serum levels of alpha1-PI determined using & only commercial immunologic assays may not accurately reflect actual functional alpha1-PI levels. Therefore, although it may be helpful to monitor serum levels of alpha1-PI in individuals receiving REFERENCES Prolastin, using currently available commercial assays of antigenic activity, results of these assays 1. Coan MH, Brockway WJ, Eguizabal H, et al: Preparation and properties of alpha1-proteinase inhibitor concentrate should not be used to determine the required therapeutic dosage. from human plasma. Vox Sang 48(6):333-42, 1985. 2. Laurell CB, Eriksson S: The electrophoretic alpha1-globulin pattern of serum in alpha1-antitrypsin deficiency. The recommended dosage of Prolastin is 60 mg/kg body weight administered once weekly. This dose Scand J Clin Lab Invest 15:132-40, 1963. is intended to increase and maintain a level of functional alpha1-PI in the epithelial lining of the lower 3. Eriksson S: Pulmonary emphysema and alpha1-antitrypsin deficiency. Acta Med Scand 175(2):197-205, 1964. respiratory tract, providing adequate anti-elastase activity in the lung of individuals with alpha1 4. Eriksson S: Studies in alpha1-antitrypsin deficiency. Acta Med Scand Suppl 432:1-85, 1965. antitrypsin deficiency. 5. Kueppers F, Black LF: Alpha1-antitrypsin and its deficiency. Am Rev Respir Dis 110(2):176-94, 1974. 6. Morse JO: Alpha -antitrypsin deficiency. N Engl J Med 299:1045-8; 1099-105, 1978. Alpha1-Proteinase Inhibitor (Human), Prolastin may be given at a rate of 0.08 mL/kg/min or greater 1 and must be administered intravenously. The recommended dosage of 60 mg/kg takes approximately 7. Black LF, Kueppers F: Alpha1-antitrypsin deficiency in nonsmokers. Am Rev Respir Dis 117(3):421-8, 1978. 30 minutes to infuse. 8. Tobin MJ, Cook PJ, Hutchison DC: Alpha1-antitrypsin deficiency: the clinical and physiological features of pul monary emphysema in subjects homozygous for Pi type Z. A survey by the British Thoracic Association. Br J Dis Parenteral drug products should be inspected visually for particulate matter and discoloration prior to Chest 77(1):14-27, 1983. administration, whenever solution and container permit. 9. Larsson C: Natural history and life expectancy in severe alpha1-antitrypsin deficiency, Pi Z. Acta Med Scand 204(5): 345-51, 1978. Safety and effectiveness in pediatric patients has not been established. 10. Pannell R, Johnson D, Travis J: Isolation and properties of human plasma alpha1-proteinase inhibitor. Biochemistry Reconstitution 13(26):5439-45, 1974. 11. Lieberman J: Elastase, collagenase, emphysema, and alpha1-antitrypsin deficiency. Chest 70(1):62-7, 1976. Vacuum Transfer 12. Gadek JE, Fells GA, Zimmerman RL, et al: Antielastases of the human alveolar structures: implications for the Note: Aseptic technique should be carefully followed. All needles and vial tops that will come into protease-antiprotease theory of emphysema. J Clin Invest 68(4):889-98, 1981. contact with the product to be administered via the intravenous route should not come in contact with 13. Beatty K, Bieth J, Travis J: Kinetics of association of serine proteinases with native and oxidized alpha-1-proteinase any nonsterile surface. Any contaminated needles should be discarded by placing in a puncture-proof inhibitor and alpha-1-antichymotrypsin. J Biol Chem 255(9):3931-4, 1980. container and new equipment should be used. 14. Janoff A, White R, Carp H, et al: Lung injury induced by leukocytic proteases. Am J Pathol 97(1):111-36, 1979. 15. Gadek JE, Crystal RG: Alpha1-antitrypsin deficiency. In: Stanbury JB, Wyngaarden JB, Frederickson DS, et al, 1. After removing all items from the box, warm the sterile water (diluent) to room temperature (25°C, eds.: The Metabolic Basis of Inherited Disease. 5th ed. New York, McGraw-Hill, 1983, p.1450-67. 77°F). 16. Larsson C, Dirksen H, Sundstrom G, et al: Lung function studies in asymptomatic individuals with moderately (Pi SZ) and severely (Pi Z) reduced levels of alpha -antitrypsin. Scand J Respir Dis 57(6):267-80, 1976. 2. Remove the plastic flip tops from each vial (Fig. A). Cleanse vial tops (grey stoppers) with alcohol 1 17. Gadek JE, Klein HG, Holland PV, et al: Replacement therapy of alpha1-antitrypsin deficiency: reversal of protease swab and allow surface to dry. After cleaning, do not allow anything to touch the latex (rubber) antiprotease imbalance within the alveolar structures of PiZ subjects. J Clin Invest 68(5):1158-65, 1981. stopper. 18. Data on file. 3. Carefully remove the plastic sheath from the short end of the transfer needle. Insert the exposed 19. Wewers MD, Casolaro MA, Sellers SE, et al: Replacement therapy for alpha1-antitrypsin deficiency associated with emphysema. N Engl J Med 316(17):1055-62,1987. needle into the diluent vial to the hub (Fig. B). 20. Wewers MD, Casolaro MA, Crystal RG: Comparison of alpha-1-antitrypsin levels and antineutrophil elastase 4. Carefully grip the sheath of the other end of the transfer needle and twist to remove it. capacity of blood and lung in a patient with the alpha-1-antitrypsin phenotype null-null before and during alpha-1 antitrypsin augmentation therapy. Am Rev Respir Dis 135(3):539-43, 1987. 5. Invert the diluent vial and insert the attached needle into the vial of concentrate at a 45° angle 21. Burrows B: A clinical trial of efficacy of antiproteolytic therapy: can it be done? Am Rev Respir Dis (Fig. C). This will direct the stream of diluent against the wall of the concentrate vial and minimize 127(2:2):S42-3, 1983. foaming. The vacuum will draw the diluent into the concentrate vial. 22. Cohen AB: Unraveling the mysteries of alpha1-antitrypsin deficiency. N Engl J Med 314(12):778-9, 1986. 6. Remove the diluent bottle and transfer needle (Fig. D). 23. Finlayson JS: Albumin products. Semin Thromb Hemost 6(2):85-120, 1980. 7. Gently swirl the concentrate bottle until the powder is completely dissolved (Fig. E). The vial 08937789 (Rev. January 2005) should then be visually inspected for particulate matter and discoloration prior to administration.

8. Clean the top of the vial of reconstituted Alpha1-Proteinase Inhibitor (Human), Prolastin again with alcohol swab and let surface dry. 9. Attach the filter needle (from the package) to sterile syringe. Withdraw the Prolastin solution into the syringe through the filter needle (Fig. F). Talecris Biotherapeutics, Inc. 10. Remove the filter needle from the syringe and replace with an appropriate injection needle for Research Triangle Park, NC 27709 USA administration. Discard filter needle into a puncture-proof container. U.S. License No. 1716 11. The contents of more than one bottle of Prolastin may be drawn into the same syringe before administration. If more than one bottle of Prolastin is used, withdraw contents from bottles using aseptic technique. Place contents into an administration container (plastic minibag or glass bottle) using a syringe. * Avoid pushing an I.V. administration set spike into the product container stopper as this has been known to force the stopper into the vial, with a resulting loss of sterility. *For a patient of average weight (about 70 kg) the volume needed will exceed the limit of one syringe.